Breyanzi

— THERAPEUTIC CATEGORIES —
  • Leukemias, lymphomas, and other hematologic cancers
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Breyanzi Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Lisocabtagene maraleucel (contains between 6.9×10^6 to 322×10^6 CAR-positive viable T cells [consisting of 1:1 CD8 and CD4 components]); per vial; cell susp for IV infusion; contains dimethyl sulfoxide (DMSO), albumin (human).

    Pharmacological Class

    CD19-directed genetically modified autologous T cell immunotherapy.

    How Supplied

    Single-dose vials (5mL)—1, 2×4

    How Supplied

    Breyanzi consists of genetically modified autologous T cells, supplied in vials as separate

    frozen suspensions of each CD8 component and CD4 component. Each CD8 or CD4 component is packed in a carton containing up to 4 vials, depending upon the concentration of the cryopreserved drug product CAR-positive viable T cells.

    Breyanzi is shipped directly to the cell lab or clinical pharmacy associated with the infusion center in the vapor phase of a liquid nitrogen shipper. A Release for Infusion Certificate for each component and patient-specific syringe labels are affixed inside the shipper.

    Storage

    Store vials in the vapor phase of liquid nitrogen (less than or equal to minus 130°C) in a temperature-monitored system.

    If the patient is not expected to be ready for administration before the shipper expires and the infusion site is qualified for onsite storage, transfer Breyanzi to onsite vapor phase of liquid nitrogen storage prior to preparation.

    If the patient is not expected to be ready for administration before the shipper expires and the infusion site is not qualified for onsite storage, contact Bristol-Myers Squibb at 1-888-805-4555 to arrange for return shipment.

    Manufacturer

    Bristol Myers Squibb

    Generic Availability

    NO

    Mechanism of Action

    Lisocabtagene maraleucel binds to CD19 expressed on the cell surface of tumor and normal B cells which induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells.

    Breyanzi Indications

    Indications

    Treatment of adults with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B who have: refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or relapsed or refractory disease after ≥2 lines of systemic therapy. Treatment of adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy including, a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor.

    Limitations of Use

    Not for treating primary CNS lymphoma.

    Breyanzi Dosage and Administration

    Prior to Treatment Evaluations

    Monitor CBC prior to and after administration.

    Pregnancy testing should be performed prior to starting treatment.

     

    Adult

    For autologous and IV use only; confirm patient identity prior to infusion. Do not use a leukodepleting filter. Give lymphodepleting chemotherapy (cyclophosphamide 300mg/m2/day IV + fludarabine 30mg/m2/day IV) for 3 days. Premedicate with APAP and diphenhydramine or other H1-antihistamine approx. 30–60mins prior to Breyanzi infusion; avoid prophylactic corticosteroids. Infuse Breyanzi 2–7 days after lymphodepleting chemotherapy. Relapsed/refractory CLL/SLL or LBCL after 1 line of therapy: give a single dose of 90–110×106 CAR-positive viable T cells (consisting of 1:1 CD8 and CD4 components), with each component supplied separately. Relapsed/refractory after ≥2 lines of therapy: give a single dose of 50–110×106 CAR-positive viable T cells (consisting of 1:1 CD8 and CD4 components), with each component supplied separately. May need >1 vial per component to achieve target dose. For dose preparation/administration and management of severe adverse reactions: see full labeling.

    Children

    Not established.

    Administration

    Confirm patient identity upon receipt of Breyanzi; the patient’s identity must match the patient identifiers on the Breyanzi cartons, vials and syringe labels. Should be administered at a REMS-certified health care facility.

    See the respective Certificate of Release for Infusion for each component, for the actual cell counts and volumes to be infused.

    Confirm tocilizumab and emergency equipment are available prior to infusion and during the recovery period.

    Confirm the infusion time in advance and adjust the start time of Breyanzi thaw such that it will be available for infusion when the patient is ready.

    Thaw BreyanziI prior to infusion; the thaw must be carried to completion and the cells administered within 2 hours. Thaw at room temperature until there is no visible ice in the vials; thaw all the vials at the same time.

    Infuse Breyanzi 2 to 7 days after completion of lymphodepleting chemotherapy. Delay the infusion if the patient has unresolved serious adverse events from preceding chemotherapies, active uncontrolled infection, or active graft-vs-host disease.

    Premedicate with acetaminiphen (650mg orally) and diphenhydramine (25-50mg IV or orally) or another H1 antihistamine, 30-60 minutes prior to treatment with Breyanzi; avoid prophylactic systemic corticosteroids as they may interfere with the activity of Breyanzi.

    A separate syringe should be prepared for each CD8 or CD4 component vial received. Prepare the syringe(s) of the CD8 component first. The total time from removal from frozen storage to patient administration should not exceed 2 hours as indicated by the time entered on the syringe label.

    Administer the entire volume of the CD8 component intravenously at an infusion rate of approximately 0.5mL/minute, using the closest port or Y-arm.

    If more than 1 syringe is required for a full cell dose of the CD8 component, administer the volume in each syringe consecutively without any time between administering the contents of the syringes.

    Administer the CD4 component second, immediately after administration of the CD8 component is complete (infusion rate of approximately 0.5mL/minute).

    Monitor patients daily for at least 7 days following infusion for signs/symptoms of cytokine release syndrome and neurologic toxicities.

    Patients should remain within proximity of the certified health care facility for at least 4 weeks following infusion.

    Breyanzi Contraindications

    Not Applicable

    Breyanzi Boxed Warnings

    Boxed Warning

    Cytokine release syndrome. Neurologic toxicities. Secondary hematological malignancies.

    Breyanzi Warnings/Precautions

    Warnings/Precautions

    Risk of cytokine release syndrome (CRS); do not give to patients with active infection and/or inflammatory disorders. Have tocilizumab and emergency equipment readily available. Monitor daily for at least 7 days at the healthcare facility following infusion for signs/symptoms of CRS and neurologic toxicities. Continue to monitor for CRS for 4 weeks after infusion; at 1st sign, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated (see full labeling). Monitor for neurologic toxicities for 4 weeks after infusion and treat promptly (see full labeling). Monitor for infection, febrile neutropenia; evaluate, manage and treat appropriately. Screen for HBV, HCV, and HIV prior to cell collection for manufacturing. Consider concurrent antiviral therapy to prevent HBV reactivation in those with prior history of HBV. Monitor CBCs (prior to and after initiation), immunoglobulin levels after treatment. Pregnancy: not recommended. Verify pregnancy status prior to initiation. Nursing mothers.

    Warnings/Precautions

    Cytokine Release Syndrome (CRS)

    • 45% (n=68/150) of patients receiving Breyanzi after 1 line of therapy for LBCL experienced CRS; median time to onset: 4 days; CRS resolved in all patients with a median duration of 4 days.
    • 46% (n=122/268) of patients receiving Breyanzi after 2 or more lines of therapy for LBCL experienced CRS; median time to onset: 5 days; CRS resolved in 98% with a median duration of 5 days.
    • Most common manifestations: fever, hypotension, tachycardia, chills, hypoxia, headache.
    • Potential for serious adverse events associated with CRS including cardiac arrhythmias (eg, atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
    • Ensure that 2 doses of tocilizumab are available prior to infusion.
    • Monitor patients daily for 7 days post infusion; monitor for CRS for at least 4 weeks.

    CRS Grading and Management Guidance

    Grading of CRS based on Lee criteria.

    If corticosteroids are initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms, and consider corticosteroid taper.

    Grade 1

    Definition: Fever

    Tocilizumab: If <72 hours after infusion, consider tocilizumab 8mg/kg IV over 1 hour (not to exceed 800mg). If ≥72 hours after infusion, treat symptomatically.

    Corticosteroids: If <72 hours after infusion, consider dexamethasone 10mg IV every 24 hours. If ≥72 hours after infusion, treat symptomatically.

    Grade 2

    Definition: Symptoms require and respond to moderate intervention. Oxygen requirement <40% FiO2, or hypotension responsive to fluids or low dose of 1 vasopressor, or grade 2 organ toxicity.

    Tocilizumab: Administer tocilizumab 8mg/kg IV over 1 hour (not to exceed 800mg). Repeat tocilizumab every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses.

    Corticosteroids: If <72 hours after infusion, administer dexamethasone 10mg IV every 12-24 hours. If ≥72 hours after infusion, consider dexamethasone 10mg IV every 12-24 hours.

    • If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (10-20mg IV every 6 to 12 hours).
    • If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total.

    Grade 3

    Definition: Symptoms require and respond to aggressive intervention. Oxygen requirement

    ≥40% FiO2, or hypotension requiring high-dose or multiple vasopressors, or grade 3 organ toxicity, or grade 4 transaminitis.

    Tocilizumab: Per grade 2.

    Corticosteroids: Administer dexamethasone 10mg IV every 12 hours.

    • If no improvement within 24 hours or rapid progression of CRS, repeat tocilizumab and escalate dose and frequency of dexamethasone (10-20mg IV every 6 to 12 hours).
    • If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total.

    Grade 4

    Definition: Life-threatening symptoms. Requirements for ventilator support or continuous veno-venous hemodialysis or grade 4 organ toxicity (excluding transaminitis).

    Tocilizumab: Per grade 2.

    Corticosteroids: Administer dexamethasone 20mg IV every 6 hours.

    • If no improvement within 24 hours or rapid progression of CRS, escalate tocilizumab and corticosteroid use.
    • If no improvement or continued rapid progression, maximize dexamethasone, switch to high-dose methylprednisolone 2mg/kg if needed. After 2 doses of tocilizumab, consider alternative immunosuppressants. Do not exceed 3 doses tocilizumab in 24 hours, or 4 doses in total.

    Neurologic Toxicities

    • 27% (n=41/150) of patients receiving Breyanzi after 1 line of therapy for LBCL experienced CAR T cell-associated neurologic toxicities; median time to onset was 8 days; median duration of neurologic toxicity was 6 days.
    • 35% (n=95/268) of patients receiving Breyanzi after 2 or more lines of therapy for LBCL experienced CAR T cell-associated neurologic toxicities; median time to onset was 8 days; median duration of neurologic toxicity was 12 days.
    • Neurologic toxicities resolved in 85% of patients.
    • Of patients developing neurotoxicity, 77% (n=105/136) also developed CRS.
    • Most common neurologic toxicities: encephalopathy, tremor, aphasia, headache, dizziness, delirium.
    • Monitor patients daily for 7 days post infusion; monitor for neurologic toxicities for at least 4 weeks.

    Neurologic Toxicity Grading and Management Guidance

    Grading neurologic toxicities based on NCI CTCAE criteria.

    Grade 1

    • Start non-sedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
    • If ≥72 hours after infusion, observe.
    • If <72 hours after infusion, consider dexamethasone 10mg IV every 12 to 24 hours for 2 to 3 days.

    Grade 2

    • Start non-sedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
    • Dexamethasone 10mg IV every 12 hours for 2-3 days, or longer for persistent symptoms. 
    • Consider taper for a total steroid exposure of >3 days.
    • If no improvement after 24 hours or worsening of neurologic toxicity increase dose and/or frequency of dexamethasone up to a maximum of 20mg IV every 6 hours.
    • If no improvement after another 24 hours, rapidly progressing symptoms, or life-threatening complications arise, give methylprednisolone (2mg/kg loading dose, followed by 2mg/kg divided 4 times a day; taper within 7 days).

    Grade 3

    • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
    • Dexamethasone 10-20mg IV every 8 to 12 hours.
    • Steroids are not recommended for isolated grade 3 headaches.
    • If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per grade 2).
    • If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy.
    • Give high-dose methylprednisolone (1-2g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5g/m2.

    Grade 4

    • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
    • Dexamethasone 20mg IV every 6 hours. 
    • If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per grade 2). 
    • If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy.
    • Give high-dose methylprednisolone (1-2g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5g/m2.

    Hypersensitivity Reactions
    Allergic reactions may occur with infusion. Serious hypersensitivity reactions may be due to DMSO.

    Serious Infections

    • Infections of any grade occurred in 36% of patients receiving Breyanzi for LBCL. 
    • Febrile neutropenia developed after infusion in 8% of patients.
    • Monitor for signs/symptoms of infection; administer prophylactic antimicrobials according to guidelines.
    • Avoid Breyanzi administration in patients with clinically significant, active systemic infections.
    • Perform screening for HBV, HCV, and HIV before collection of cells for manufacturing. 
    • Patients with prior history of HBV: consider concurrent antiviral suppressive therapy to prevent reactivation.

    Prolonged Cytopenias

    • Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and Breyanzi.
    • These included thrombocytopenia, neutropenia, and anemia.
    • Monitor CBC prior to and after administration of Breyanzi.

    Hypogammaglobulinemia

    • B-cell aplasia and hypogammaglobulinemia can occur in patients receiving Breyanzi.
    • Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

    Secondary Malignancies

    • Patients treated with Breyanzi may develop secondary malignancies.
    • Monitor lifelong for secondary malignancies.
    • Contact BMS (888) 805-4555 to report secondary malignancies.

    Effects on Driving, Using Machines

    • Patients on Breyanzi are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following administration.
    • Patients should refrain from driving or engaging in hazardous occupations or activities (eg, operating heavy machinery) for at least 8 weeks.

    Immunogenicity

    • Breyanzi has the potential to induce anti-product antibodies.
    • The relationship between anti-product antibody status and efficacy, safety, or pharmacokinetics has not been established.

    Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS)

    • IEC-HS, including fatal or life-threatening reactions, occurred following treatment.
    • Treatment of IEC-HS should be administered per current practice guidelines.

    Pregnancy Considerations

    There are no available data with Breyanzi use in pregnant women. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia and hypogammaglobulinemia. Breyanzi is not recommended for pregnant women and pregnancy after infusion should be discussed with the treating physician.

    Nursing Mother Considerations

    There is no information regarding the presence of Breyanzi in human milk, the effect on the breastfed infant, and the effects on milk production. Consider the benefits for the mother vs the potential risks to the infant.

    Pediatric Considerations

    The safety and efficacy of Breyanzi have not been established in pediatric patients.

    Geriatric Considerations

    No clinically important differences in safety or effectiveness of Breyanzi were observed between patients aged ≥65 and younger patients.

    Other Considerations for Specific Populations

    Pregnancy status should be verified prior to treatment. There is insufficient data to provide recommendations concerning duration of contraception following Breyanzi treatment.

    There are no data on the effects of Breyanzi on fertility. 

    REMS

    YES

    Breyanzi Pharmacokinetics

    See Literature

    Breyanzi Interactions

    Interactions

    Concomitant live virus vaccines: not recommended for ≥6 weeks prior to lymphodepleting chemotherapy, during Breyanzi treatment, and until immune recovery. May cause false (+) results in certain HIV nucleic acid tests.

    Breyanzi Adverse Reactions

    Adverse Reactions

    Fatigue, fever, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, edema; hypersensitivity reactions, HBV reactivation, hypogammaglobulinemia, neurologic toxicities, prolonged cytopenias, secondary malignancies (monitor), Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IECHS).

    Breyanzi Clinical Trials

    Clinical Trials

    Relapsed or Refractory LBCL After 1 Line of Therapy

    The approval was based on data from the randomized, open-label phase 3 TRANSFORM study (ClinicalTrials.gov Identifier: NCT03575351), which evaluated the efficacy and safety of Breyanzi in 184 adults with relapsed or refractory LBCL within 12 months of first-line chemoimmunotherapy. Patients were randomly assigned 1:1 to receive either a single infusion of Breyanzi or standard therapy consisting of 3 cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT. 

    The primary endpoint was event-free survival (EFS) as determined by an independent review committee. Key secondary endpoints included complete response (CR) rate and progression-free survival (PFS).

    Results showed that patients in the Breyanzi treatment arm achieved the following improvements vs those in the standard therapy arm, respectively:

    • EFS: 10.1 months vs 2.3 months (hazard ratio [HR], 0.34; 95% CI, 0.22-0.52; P <.0001).
    • CR rate: 66% (95% CI, 56-76) vs 39% (95% CI, 29-50) (P <.0001); median duration of CR was not reached (NR) in the Breyanzi arm (95% CI, 7.9-NR).
    • Median PFS: 14.8 months vs 5.7 months (HR, 0.41; 95% CI, 0.25-0.66; P =.0001).

    The efficacy of Breyanzi in the second-line setting was also supported by data from the single-arm, open-label, phase 2 PILOT trial (ClinicalTrials.gov Identifier: NCT03483103), which included 61 transplant-ineligible patients with relapsed or refractory LBCL after 1 line of chemoimmunotherapy. Findings showed an overall response rate of 80% (primary endpoint); 54% of patients achieved CR while 26% had a partial response. The median time to CR was 1 month (range, 0.8-6.9 months) and the median duration of response was 11.2 months (95% CI, 5.1-NR).

    Relapsed or Refractory LBCL After 2 or More Lines of Therapy

    The approval was based on data from a pivotal phase 1 study (TRANSCEND; ClinicalTrials.gov Identifier: NCT02631044) that assessed the efficacy and safety of Breyanzi in patients with relapsed or refractory large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. The primary outcome measures included treatment-related adverse events, dose-limiting toxicities and objective response rate (ORR). Key secondary end points included complete response rate, duration of response (DoR), and progression-free survival (PFS). 

    Among 192 patients in the main efficacy population, the ORR was 73% (95% CI, 67-80), of which 54% of patients (95% CI, 47-61) had complete response (CR) and 19% (95% CI, 14-26) had partial response (PR). The median DoR was 16.7 months (95% CI, 5.3-NR) among all responders; the median DOR was not reached (95% CI, 16.7-NR) among responders who achieved a CR; and the median DoR was 1.4 months (95% CI, 1.1-2.2) among responders who achieved a best response of PR. Of the 104 patients who achieved CR, 65% had remission lasting at least 6 months and 62% had remission lasting at least 9 months.

     

    Relapsed or Refractory LBCL After Two or More Lines of Therapy

    The approval was based on data from the open-label, single-arm, phase 1/2 TRANSCEND CLL 004 study (ClinicalTrials.gov Identifier: NCT03331198) which evaluated the efficacy and safety of liso-cel in adults with relapsed or refractory CLL or SLL after progression on a BTKi and BCL-2 inhibitor. Efficacy was based on overall response rate (ORR), including complete response rate (CR), partial response (PR), and duration of response (DOR) as determined by an independent review committee. 

    Results showed that 20% (95% CI, 11.1-31.8) of patients treated with liso-cel achieved a CR. Among those who achieved a CR, median DOR was not reached and the minimal residual disease (MRD)-negativity rate was 100% (n=13/13; 95% CI, 75.3-100) in peripheral blood and 92.3% (n=12/13; 95% CI, 64-99.8) in the bone marrow. Moreover, the ORR was 45% (95% CI, 32.3-57.5) and the median DOR was 35.3 months (95% CI, 12.4-not reached) among all responders. 

    Breyanzi Note

    Notes

    Available only through a restricted REMS Program. For more information visit www.BreyanziREMS.com or call (888) 423-5436.

    Breyanzi Patient Counseling

    Patient Counseling

    Ensure that patients understand the risk (11%) of manufacturing failure. Additional bridging therapy may be necessary while the patient awaits the product. This bridging therapy may be associated with adverse events during the pre-infusion period, which could delay or prevent the administration of Breyanzi.

    Daily monitoring for at least 7 days following Breyanzi is required. Patients should remain within 2 hours of a REMS-certified health care facility for at least 4 weeks following the infusion.

    Advise patients of the risks associated with treatment: CRS, neurologic toxicities, serious infections, prolonged cytopenias.

    If diagnosed with a secondary malignancy, contact BMS (888) 805-4555.

    Refrain from driving or operating heavy machinery until at least 8 weeks after Breyanzi administration.

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